Diabetes in children

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jaspinder Kaur, MBBS[2]

Synonyms and keywords: Pediatric Diabetes Mellitus (DM)

Overview

Diabetes mellitus (DM) is the metabolic homeostasis disorder regulated by insulin which causes abnormalities in the carbohydrate and lipid metabolism. Type 1 diabetes (also called juvenile-onset diabetes mellitus, DM1, T1DM, and insulin-dependent diabetes mellitus) is considered an immuno-mediated disease that results in a gradual destruction of insulin-producing pancreatic beta cells, and subsequently leads to their complete loss and total dependence on exogenous insulin. The etiology and natural history of T1DM are not yet completely known; however, the genetic and environmental factors are likely responsible for the underlying damage. The genetic effect probably contributes 70 to 75% in the susceptibility to T1DM; while, environmental factors possibly initiates or stimulates the process resulting in the destruction of the beta cells and the disease onset. The disease process begins months to years before the onset of clinical signs such as polyuria, polydipsia, weight loss, and diabetic ketoacidosis. Clinical presentation usually begins at any age; however, most patients will be diagnosed before the age of 30 years. Type 2 diabetes mellitus (T2DM) is characterized by two underlying defects. The earliest abnormality being an insulin resistance which initially compensated with an increase in insulin secretion. Thereafter, T2DM develops due to a defect in insulin secretion that prevents such secretion from matching the increased requirements imposed by an initial insulin-resistant state. Therefore, T1DM results from an absolute insulin deficiency, and relative deficiency in T2DM. Although, the percentage of DM cases in children and adolescents caused by T2DM has risen in the past 1 to 2 decades; however, T1DM remains the most common form of DM in children. Acute and chronic complications including renal failure, retinopathy, neuropathy, and cardiovascular disease are related to and likely caused by the hyperglycemic state. Recombinant insulin analogs, insulin pumps, and newer devices for home monitoring have drastically improved the ability to control glucose concentrations in patients with DM. However, the feedback control in the healthy state that allows minute-to-minute regulation of insulin secretion cannot be recapitulated with current diabetes therapies; thereby achieving the full metabolic normalization not yet possible and making some degree of hyperglycemia persists in virtually all patients with diabetes.

Historical Perspective

• 400–500 A.D.: Indian physicians named it madhumeha (‘honey urine’) as ants are attracted by urine sweetness. The ancient Indian physician, Sushruta, and the surgeon Charaka discovered the two forms of DM which are later classified as Type I and Type 2 diabetes.
• 1889: Von Mering and Minkowski while experimenting on dogs found that removal of the pancreas led to diabetes.
• 1921: Banting, Best and Collip while working in Macleod’s laboratory ligated the pancreatic duct which resulted in the destruction of the exocrine pancreas while leaving the islets intact. They used canine insulin extracts in their animal experiment to reverse induced diabetes; and thereby, conclusively established that the deficiency of insulin was the cause of diabetes.
• 1922: The discovery of insulin by Canadian surgeon Banting and his assistant Best was made. Following experimentation on dogs, their life-saving infusion of a bovine extract of insulin developed by their biochemist colleague, Collip to a 14-year-old boy, Leonard Thompson, in 1922 at the Toronto General Hospital emerged as a sensation in the world of diabetic therapy.
• 1960-1969: Urine strips in the 1960s and the automated ‘doit-yourself’ measurement of blood glucose through glucometers produced by Ames Diagnostics in 1969 brought glucose control from the emergency room to the patient’s living room.
• 1980: Graham Bell manufactured the first human insulin.
• 1982: The first biosynthetic insulin (humulin) was developed by Eli Lilly.
• 1986: Eisenbarth proposed the pathophysiological model of T1DM as a gradual deficiency of insulin production resulting from the autoimmune T cells mediated destruction of pancreatic beta cells in individuals genetically susceptible to the disease who were born with a normal number of beta cells; but undergo a process of cell destruction after being exposed to the precipitating environmental factors.
• November 14: Since 2007, Banting’s colossal contribution has been globally recognized by the declaration of his birthday on November 14 as the World Diabetes Day.

Classification

Diabetes mellitus in children has been classified into the following forms:

• Type 1 Diabetes mellitus (T1DM)
• Type 2 Diabetes mellitus (T2DM)
• Monogenic diabetes: Neonatal diabetes, MODY-maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes
• Diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs
• Diabetes related to certain genetic syndromes

Table 1: Characteristics of prevalent forms of primary diabetes in children and adolescents

Features	Type 1 diabetes	Type 2 diabetes	MODY*	Atypical diabetes**
Prevalence	~85%	~12%	~1–4%	≥10% in African American
Age at onset	Throughout childhood and adolescence	Puberty; rare ‹10 years	‹25 years	Pubertal
Onset	Acute severe	Insidious to severe	Gradual	Acute severe
DKA at onset	~30%	~6%	Not typical	Common
Affected relative	5–10%	60–90%	50–90%	›75%
Female:male	1:1	1.1–1.8:1	1:1	Variable
Inheritance	Polygenic	Polygenic	Autosomal dominant	Autosomal dominant
HLA-DR3/4	Association	No association	No association	No association
Ethnicity	All, Caucasian at highest risk	All¶	All	African American/Asian
Insulin (C-peptide) secretion	Decreased/absent	Variable	Variably decreased	Variably decreased
Insulin sensitivity	Normal when controlled	Decreased	Normal	Normal
Insulin dependence	Permanent	Variable	Variable	Intermittent
Obesity	No†	›90%	Uncommon	Varies with population
Acanthosis nigricans	No	Common	No†	No†
Islet autoantibodies	Yes§	No	No	No

• *MODY is maturity-onset diabetes in the young or monogenic diabetes.
• **Atypical diabetes is also referred to as Flatbush diabetes, type 1.5 diabetes, ketosis-prone diabetes, and idiopathic T1DM.
• ¶In North America, T2DM predominates in African American, Hispanic, Native American, and Canadian First Nations children and adolescents; and is also more common in Asian and South Asian than in Caucasian individuals.
• †Mirrors rate in general population.
• §Diabetes-associated (islet) autoantibodies to insulin, islet cell cytoplasmic, glutamic acid decarboxylase, or tyrosine phosphatase (insulinoma-associated) antibody (IA-2, ICA512, ZnT8 antibodies in 85–95%) at diagnosis.

Pathophysiology

Type 1 Diabetes Mellitus

• Immune-mediated process:
  • The autoimmune destruction of beta cells probably occurs over the course of months to years before diabetes develops.
  • ›80% of beta cells must be lost before significant glycemic control gets impaired.
  • As beta-cell loss progresses beyond that point, insulin is insufficiently secreted to maintain glucose and lipid homeostasis.
  • When glucose concentrations in the blood rise above ~180 mg/dL (10.0 mmol/L), glucosuria occurs leading to an osmotic diuresis that causes polyuria which further stimulates polydipsia to maintain euvolemia.
  • With further progression of insulin deficiency, there is an increase in lipolysis from fat cells as well as protein breakdown; thereby exaggerating the normal fasting state designed to provide alternative sources of fuel.
  • These complex mechanisms along with the caloric loss from glucosuria result in the hyperphagia and weight loss typical of the underlying undiagnosed diabetic state.
  • With profound insulin deficiency, the process devolves into ketoacidosis with marked hyperglycemia, dehydration driven by the glucosuric osmotic diuresis, and accumulation of ketoacids from the hepatic metabolism of the liberated fatty acids.
  • Hence, insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death.
• The Diabetes Control and Complications Trial (DCCT) was the pivotal study published in 1993 documenting the clear association of chronic hyperglycemia with long-term microvascular complications such retinopathy, neuropathy, and microalbuminuria (as a surrogate for nephropathy). Follow-up studies have documented the association of chronic hyperglycemia with macrovascular complications as well as all-cause mortality. Iatrogenic hypoglycemia, however, was identified as the major limiting factor to intensive glucose control.

Type 2 Diabetes Mellitus

• Obesity leads to peripheral insulin resistance and subsequently hyperglycemia. Apart from obesity, certain ethnicities carries higher risks of insulin resistance and beta cell dysfunction. Thereby, hyperglycemia leads to an osmotic diuresis (polyuria) which increases thirst (polydipsia); and this subsequent diuresis causes moderate to severe dehydration. Hence, prolonged hyperglycemia can produce two distinct emergent states in children with T2DM.
• Diabetic ketoacidosis: It is much more common in children with T2DM than adults. Lack of insulin inhibits the body's ability to use glucose for energy and reverts to breaking down fat for energy. This leads to ketosis, acidosis, and electrolyte abnormalities and may lead to coma and death.
• Hyperglycemic Hyperosmolar State (HHS): It is characterized by hypertonicity, extreme hyperglycemia (> 600 mg/dl), and severe dehydration resulting from continued osmotic diuresis and intravascular depletion.

Etiology

Type 1 Diabetes Mellitus

• Both genetic and environmental factors lead to immune-mediated loss of beta cell functions resulting in hyperglycemia and life-long insulin dependence. A "triggering" insult in the form of maternal and intrauterine environment, exposure to viruses, host microbiome, diet and many other factors are thought to contribute towards disease susceptibility by initiating a process that recruits antigen-presenting cells to transport beta cell self-antigens to autoreactive T cells. Through failures of self-tolerance, these T cells mediate beta-cell killing and inflammation leading to insulinopenia and symptomatic DM.
• Recently, preclinical stages of T1DM have been discovered and divided into 3 different stages as described in the following Table 2.

Table 2: Staging of T1DM

Stage	Features
Stage 1	Pre-symptomatic DM1: It corresponds to the immunological disease phase with a positive autoimmunity which may progress to the clinical disease over a period of 8 to 10 years. Diagnostic criteria: ›2 autoantibodies against the islet; No IGT or IFG; Normal blood glucose level
Stage 2	Pre-symptomatic DM1: It corresponds to the almost irreversible stage of the disease with functional loss of beta cells and the beginning of metabolic disease with positive autoimmunity (two or more autoantibodies against the islet) and pre-diabetic dysglycemia. The risk of symptomatic disease within a period of 5 years is approximately 75%, reaching 100% over a lifetime. Diagnostic criteria: ›2 autoantibodies; Dysglycemia: IFG and/or IGT; FPG 100–125 mg/dL (5.6–6.9 mmol/L); 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L); A1C 5.7–6.4% (39–47 mmol/mol) or ≥10% increase in A1C
Stage 3	Symptomatic DM1: It corresponds to the autoimmune acceleration stage of the disease with positive autoimmunity (two or more autoantibodies against the islet) and diabetic dysglycemia (diabetic fasting glucose and/or diabetic OGTT, increase in HbA1c). Progression of the symptomatic phase of DM1 can further be classified as following: Initial phase); Established DM1 phase; Established DM1 phase with chronic complications Diagnostic criteria: Clinical symptoms; Diabetes by standard criteria

• Although the pre-clinical staging is not usually clinically relevant and progression through these stages may take years; however, research focusing on interventions in the pre-clinical groups may prove to delay or prevent the onset of T1DM.

Type 2 Diabetes Mellitus

• Insulin resistance state initially leads to an increased insulin production by the remaining beta cells of the pancreas. When the beta cells are unable to produce enough insulin to maintain euglycemia, hyperglycemia results. Thereby, hyperglycemia results when there is a relative lack of insulin production compared to glucose levels in the blood which put damaging effects to multiple organs, including kidneys, eyes, heart, and nerves; and further puts children at risk for other electrolyte disturbances.

Differentiating Diseases

• Salicylate toxicity
• Pheochromocytoma
• Diabetes insipidus
• Hyperthyroidism

Epidemiology and Demographics

Type 1 Diabetes Mellitus

• Age: It may be diagnosed at nearly any age, though peaks in presentation occur between ages 5 to 7 and around puberty.
• Gender: Unlike most autoimmune disorders, T1DM is slightly more common in boys and men.
• Incidence and prevalence: In the past several decades, it has increased in most age, sex, and race/ethnic groups with some of the rapid growth in young children. There is significant variability in incidence based on geography and ethnicity. For example, the incidence in Finland is 60 per 100,000 person-years, while in China it is 0.1 per 100,000. In the United States, the general population risk is ~0.3% with ~20 to 30 new diagnoses per 100,000 person-years; thereby leaving more than 1.25 million people and around 500,000 children living with T1DM. These incidences have increased by 200% to 300% in the past several decades.
• Seasonal variation: There appears to be seasonal variation with more cases diagnosed in fall and winter.
• Family association: If a child has T1DM, concordance in another sibling is around 5%. In fraternal twins, it is around 10% to 30%, and with identical twins, it is 40% to 50%. Children of adults with T1DM are at an approximately 5% to 8% risk.

Type 2 Diabetes Mellitus

• It is estimated to occur in one in three (20% to 33%) of new diagnoses of diabetes in children today.
• The rate continues to rise even as the obesity rates have plateaued in these age groups.
• Risk factors: High-risk ethnicity (African American, Hispanic, Native Americans, Pacific Islanders, Asian Americans), a positive first-degree relative with the disorder, obesity, low birth weight, mother with gestational DM, and female sex. It is more likely to be diagnosed during adolescence when insulin resistance is common due to multiple factors including hormonal changes.

Risk Factors

Type 1 Diabetes Mellitus

• Genetics:
  • Type of inheritance still remains unknown despite of knowing HLA genes and other genes contributing to the genetic effect.
  • Currently, the main markers of susceptibility to T1DM are considered to be class II HLA haplotypes DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2 serotype) and DRB1*0401-DQA1*0301-DQB1*0302 (DR4-DQ8 serotype), while DRB1*0403 is negatively associated with T1DM, and may protect or slow the progression to clinical disease.
  • Genes such as IL2, CD25, INS, IL18RAP, IL10, IFH1, and PTPN22 appear to exert an influence on the speed of progression to T1DM after the onset of autoimmunity against the islet; and predictive algorithms for T1DM that also incorporated non-HLA genetic markers such as the PTPN22 or the INS gene increased the capacity to predict risk, especially in individuals with the DR3/DR4 haplotype in the general population.
  • Genome-wide association studies have already identified more than 40 gene loci associated with the T1DM phenotype involved in autoimmunity, the production and metabolism of insulin, and the survival of the pancreatic beta cells.
  • Recurrence among siblings of a patient with T1DM1 5%, which means a risk 15 times higher, reaching 65-70% between monozygotic twins, or even higher if the index case has developed the disease in childhood.

• Environmental:
  • Risk factors such as early fetal events, viral infections during the intrauterine or postnatal period, early exposure to the components of cow’s milk, and attending day care as indicative of early infections could trigger the autoimmune process.
  • Maternal risk factors includes advanced maternal age, birth by cesarean section, and lower birth order.
  • Socioeconomic status: The frequency of T1DM in childhood has been associated with estimates of the wealth of populations, such as the gross domestic product, suggesting that lifestyle habits related to wealth may be responsible for changes in these trends.
  • However, the role of the metabolism of vitamin D remains unclear.

Natural History and Prognosis

• Natural history: It involves an increased risk for acute and severe complications alongwith chronic microvascular and macrovascular complications that negatively affect the quality of life and survival of diabetic patients. A prompt diagnosis and appropriate therapy is important as the risk of diabetes-related complications is related to the duration of the disease. Moreover, the psychosocial impact of living with diabetes can be a challenge for any child and any family; and is particularly burdensome to those with maladaptive coping skills which can sometimes manifest as poor glycemic control.
• Prognosis: T1DM has high morbidity and mortality. The life expectancy is reduced by 10-20 years for many individuals; and ~1 million people die every year as a result of diabetes, two-thirds of which lives in the developing countries. About one-third of patients with newly-diagnosed T1DM present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5% despite aggressive treatment.

Complications

• Acute complications: Diabetic Ketoacidosis (DKA) and hypoglycemia are the most significant acute complications of diabetes and its treatment which poses a significant risk of morbidity and mortality.
• Chronic complications:
  • Both the microvascular and macrovascular complications, which generally take decades for clinically significant presentations to appear, are related to the duration of diabetes and hyperglycemia that persists even with disease treatment.
  • Although some late adolescents with an early onset of DM may show early evidence of complications (eg, nonproliferative retinopathy, microalbuminuria [urinary albumin excretion of 30 to 300 mg/d], or changes in nerve conduction); however, it is extremely uncommon for a child to have significant diabetic microvascular or macrovascular complications. Therefore, glycemic control should be maximized in diabetic children to minimize their risk of long-term complications as they age.
• Risk reduction:
  • Clinical trials, including the DCCT, have demonstrated that the lower the HbA1c levels which reflects a lower average blood glucose concentration, and hence, the lower the risk of microvascular complications.
  • An improvement in HbA1c of 1% (reflecting a decrease in mean glucose concentrations of 30 to 35 mg/dL [1.67 to 2.9 mmol/L]) decreases the risk of long-term complications by approximately 20% to 50%. There is no threshold for this effect; that is, a lower HbA1c always is better in terms of lowering the risk of long-term complications.
  • However, the absolute risk reduction is less at lower HbA1c values, and lower average glucose values increase the risk of the acute complications of hypoglycemia. Therefore, diabetes management involves a balancing of the long-term benefit of lowering the average glucose concentration with avoiding the acute complication of hypoglycemia.

Hypoglycemia

• Hypoglycemia: A blood glucose concentration of ‹60 mg/dL (3.3 mmol/L) which occurs frequently in T1DM. It is caused by the inability to match the minute-to-minute changes in insulin requirements with current therapy; thereby resulting in periods when insulin action exceeds insulin requirements. Therefore, patients who have lower average blood glucose concentrations may have more frequent episodes of hypoglycemia.
• Clinical presentation: It's severity depends upon both the degree of hypoglycemia and the rapidity of its development. The adrenergic symptoms include sweating, trembling, hunger, and palpitations; and the neuroglycopenic symptoms include headache, lightheadedness, dizziness, diplopia, and confusion. Coma and seizures can occur in severe hypoglycemic episode.
• Treatment: Hypoglycemia in infants and young children and moderate reactions resulting in confusion in older children require that caregivers, teachers, coaches, and others be prepared to assist in the recognition and treatment of hypoglycemia.
  • Mild-to-moderate cases: Treated by ingesting 10 to 15 g of glucose (eg, 4 oz of juice or nondiet soft drink).
  • Severe cases: Intramuscular or subcutaneous glucagon (1 mg, except for infants ‹10 kg, in whom 0.5mg is given).
  • A source of glucose snack (eg, a tube of cake frosting) and a glucagon emergency kit always should be available to treat it as hypoglycemia can occur away from home.

Ketonemia and Ketonuria

• Indications: The presence of urine or blood ketones should be assessed in the following conditions:
  • Persistent and significant hyperglycemia (eg, blood glucose ›250 mg/dL [13.9 mmol/L]) in spite of the administration of corrective doses of insulin
  • Child feels ill particularly with nausea and vomiting.
• Treatment: Persistent vomiting, or a refusal or inability to take fluids or food orally, requires an emergency department or office visit. Aggressive treatment with additional insulin is necessary once ketosis develops to prevent deterioration into DKA.
  • Rapid-acting insulin at doses of 10% to 20% of the total daily requirement should be given every 3 to 4 hours until the ketones are cleared.
  • Extra fluids are given to maintain hydration and excrete excess glucose and ketoacids.
  • Blood glucose and ketones should be measured frequently at least every 3 to 4 h.
  • During some illnesses, the usual daily insulin doses, adjusted for intake and glucose concentrations, can be continued.
  • For illnesses with disrupted oral intake and ketones development; treat with more frequent small doses of insulin; typical doses may be 5-10% of the total daily dose every 3 to 4 hours and further increasing to 10-20% of the total daily dose every 3 to 4 hours if ketones are present.
  • Hypoglycemic episodes:
    • Care must be taken to avoid causing hypoglycemia in a child who is not able to take sufficient caloric intake due to illness.
    • If solid foods cannot be eaten, sugar-containing foods such as soda, juice, gelatin dessert, and popsicles can be given to maintain some caloric intake and prevent hypoglycemia.
    • Glucagon: The usual dose must be administered for significant hypoglycemia during an illness. Because such doses frequently cause significant nausea and vomiting, and thereby further compromising the ability to ingest food. Hence, smaller doses may be more effective for less severe hypoglycemia due to poor intake: 10 mcg/year of age (minimum 20 mcg, maximum 150 mcg); and a repeat at twice the dose can be attempted if there is no response in 30 minutes.

Diabetes Ketoacidosis

• DKA is a state of metabolic decompensation resulting from profound insulin deficiency.
• It must be considered in a child who is not known to have diabetes but presenting with vomiting and dehydration particularly in the presence of an altered sensorium or in the absence of other indicators of a viral infection such as fever and diarrhea. It should be always considered in cases where there is a preceding history of polydipsia and polyuria.
• Ketotic episode: For a diabetic child, ketones should be measured when the child is significantly ill, if there is vomiting, or if there is persistent hyperglycemia. During a ketotic illness, referral for medical care should be considered if the patient begins to vomit. Medical attention is necessary if the patient has deep respirations or is unable to stand. Early identification and treatment are key to minimizing the further risks and complications.

Associated autoimmune disease

• Thyroid dysfunction: It occurs with greater frequency in individuals with T1DM. Thyroid-stimulating hormone (TSH) should be ordered shortly after diagnosis of DM and may be measured subsequently every 1 to 2 years. TSH should be also measured whenever any thyroid-related signs or symptoms develops. Thyroxine concentrations and thyroid antibodies also may be assessed.
• Celiac disease: It also occurs more frequently in children with T1DM. All patients should be screened at least once and any time poor growth and gastrointestinal symptoms reported. Tissue transglutaminase and antiendomysial antibodies are more sensitive and specific than antigliadin antibodies. Moreover, it is important to assure that the individual patient is not IgA-deficient by measuring IgA concentrations because these are immunoglobulin A (IgA) antibodies.

Growth Disturbance

• Height and weight should be measured at every appointment and plotted on growth curves so deviations from normal velocities can be detected early.
• Decreased growth velocity, crossing percentiles downward for height and weight, eventual short stature, and delayed skeletal and sexual maturation are associated with chronic undertreatment with insulin. Thus, a linear growth is affected negatively by poor diabetic control.
• Mauriac syndrome or diabetic dwarfism: An extreme form of this effect occurs rarely but usually associated with hepatomegaly
• Alternatively, treatment with excessive insulin doses often leads to excessive weight gain; thereby causing the weight curve to cross percentiles upward.
• Hence, maintenance of normal growth curves for height and weight is an important goal of diabetes management.

Retinopathy

• It is usually not seen before 5-10 years of diabetes duration.
• Risk factors: Poor metabolic control, elevated blood pressure, smoking, albuminuria, and elevated lipid values.
• Recommendations: ADA recommends the first ophthalmologic examination once the child is at least 10 years old and/or has had diabetes for 3 to 5 years. Then, yearly follow-up examinations are suggested.

Nephropathy

• All patients with T1DM should be monitored by urine microalbumin determination atleast annually beginning after the child is 10 years old and has had diabetes for 5 years due to the higher likelihood of developing end-stage renal disease which might necessitates dialysis or transplantation.
• Hypertension accelerates the progression of nephropathy; therefore, blood pressure should be monitored several times a year and hypertension should be treated aggressively.
• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended for treatment of hypertension.
• Microalbuminuria (30-299 mg of albumin per gram of creatinine on spot urine) is a marker for early nephropathy. Two of three urine specimens that have elevated values, measured on different days, are needed for confirmation. Patients should avoid other risk factors for nephropathy such as smoking, NSAIDs, etc.
• If hypertension, overt proteinuria, or elevation in serum creatinine or urea nitrogen values is found; renal functions should be done several times each year and consultation with a nephrologist are warranted.

Neuropathy

• Symptomatic diabetic neuropathy, peripheral or autonomic, is uncommon in children and adolescents with T1DM.
• Changes in nerve conduction may be seen after 4-5 years of having diabetes; and thereby increasing the risk of development of neuropathy with the duration of disease and degree of hyperglycemia. Hence, improvements in glycemic control may improve neuropathic symptoms.

Macrovascular Complications

• T1DM patients tend to have coronary artery, cerebrovascular, and peripheral vascular disease more often, at an earlier age, and more extensively than the nondiabetic population. Hypertension, elevated blood lipid concentrations, and cigarette smoking are other risk factors for developing macrovascular complications.
• Risk factors should be analyzed including lipid panels, blood pressure measurements, and determination of smoking status, and treatment instituted as indicated.
• Studies have show that lower lowdensity lipoprotein (LDL) values are beneficial in lowering the risk of vascular disease and recommendations continue to evolve.
• Recommendations:
  • Screening with fasting lipid measurements should begin as the following:
    • Children at age 12 years with no concerning family history; or
    • At the time of diagnosis after establishing metabolic control in cases with a positive family history for lipid abnormalities or early cardiovascular events.
  • Current recommendation goal is to achieve an LDL value below 100 mg/dL (2.59 mmol/L); and to treat the following:
    • Children older than age 10 years who have LDL cholesterol concentrations at or above 160 mg/dL (4.14 mmol/L); or
    • LDL value is at or above 130 mg/dL (3.37 mmol/L) if other risk factors are present.
• Bile acid sequestrants may be recommended as the first treatment in children; however, they are poorly tolerated and effective therapeutic data are lacking. Thus, statins should be considered with appropriate monitoring.
• Additionally, dietary counseling and blood glucose control are important parts of management.

Diagnosis

Diagnostic Criteria

• Metabolic tests predicting insulin secretion ability, glycemic state, the functional reserve of beta cells, and the clinical onset of T1DM are as follows:
  • Intravenous glucose tolerance test (IGTT);
  • Oral glucose tolerance test (OGTT);
  • Glycated hemoglobin concentrations (HbA1c).
• The American Diabetes Association (ADA) recommends the following diagnostic criteria for the diagnosis of glucose disorders in Table 3

Table 3: Diagnostic criteria of glucose disorders according to the American Diabetes Association (ADA) – 2016

Diagnosis	Fasting blood glucose (mg/dL)	2H-OGTT (mg/dL)	HbA1c (%)
Normal	70 to 99	< 140	4.5 to 5.6
Prediabetes	100 to 125	140 to 199	5.7 to 6.4
Diabetes mellitus	≥ 126	≥ 200	≥ 6.5

• 2H-OGTT: 120 minute time of the oral glucose tolerance test;
• HbA1c: glycated hemoglobin evaluated by laboratory test aligned with the Diabetes Control and Complications Trial (DCCT).

History and Physical Examination

• Presenting signs and symptoms: Polyuria, polydipsia and weight loss for days to months. Re-emergence of bedwetting, nocturia, and a need to leave classes in school to use the bathroom are complaints that suggest polyuria. However, some children may present with ketoacidosis associated with the smell of ketones, dehydration, abdominal pain, Kussmaul breathing, vomiting, coma and altered mental status.
• T2DM: These children most often present during asymptomatic screening. Children with T2DM are more likely than adults with the disorder to present in DKA (5% to 13%), especially if they are of ethnic minority descent. Adolescents with T2DM may also present in Hyperosmolar Hyperglycemic State (HHS).
• Follow up H&P: A medical provider will assess changes in diabetes status and life circumstances affecting diabetes management, for example, school experience, changes in patterns of exercise and diet, the developmental stage of the child, their participation in diabetes care tasks, family and home life changes, and adherence to therapy. It also focus on assessing issues related to glucose monitoring, insulin delivery (e.g., lipodystrophy, skin tolerance to medical adhesives on diabetes technology), and screening for symptoms of associated medical issues such as thyroid dysfunction or celiac disease.

Diagnostic Evaluation

• Screening criteria: The American Diabetes Association (ADA) recommends screening for T2DM every three years starting at ten years of age or puberty onset for the following patients:
  • Obese (body mass index (BMI) greater than or equal to the 95th percentile for age)
  • Overweight (BMI greater than or equal to the 85th percentile or > 120% ideal body weight)
  • Two risk factors which includes positive family history, high-risk ethnicity, signs of insulin resistance (polycystic ovary syndrome (PCOS), acanthosis, symptoms), or history of maternal gestational DM.

• Diagnostic criteria:
  • Random plasma blood glucose 200 mg/dl or greater with symptoms of polyuria, polydipsia, or weight loss.
  • Fasting blood glucose of 126 mg/dl or higher in an asymptomatic patient.
  • Oral glucose tolerance test with blood sugar 200 mg/dl or greater at two hours post ingestion.
  • Hemoglobin A1c > 6.5%.

• Doubtful diagnosis: Laboratory tests such as fasting insulin or C peptide (both usually high or normal in T2DM, and low in T1DM); and autoantibodies for T1DM can be ordered to differentiate between T1DM and T2DM. However, Islet cell antibodies are only found in about 5% of children and are not specific markers; hence, they are not usually measured to make the diagnosis of T1DM.
• Multidisciplinary screening: Regular screening for lipid disorders, microalbuminuria, retinopathy, thyroid disorders and celiac disease are recommended based on the duration and status of diabetes control. Assessment of mental health and psychosocial factors are equally important.

Treatment

• The management requires a diabetes healthcare team consisting of the medical provider, nurse, diabetes educator, dietician, social worker, and psychologist. However, not all specialties are always available, convenient, or covered by insurance.
• During an initial phase of management, frequent contact between the child and family and medical team through in-office visits is required while being treatment is adjusted; and the family learns the daily management tasks of caring for a child with diabetes as it needs a long-term day to day treatment decisions.
• Social worker: Involved to ensure that the child has adequate support and finances for treatment.
• Exercise specialist: Teach the child about beneficial exercises.
• Diabetic nurse: Assess the child's growth, blood pressure and injection site at every home visit; and assist with the care coordination between the patient and family with the medical providers. A mental health nurse provide counseling if a child with diabetes become depressed.
• All diabetics should be referred to an ophthalmologist, nephrologist, cardiologist and a neurologist for baseline workup of their respective organ systems.

Type 1 Diabetes Mellitus

• Insulin delivery: It is done by multiple daily injections (MDI) or an insulin pump to simulate endogenous insulin physiology.
  • Multiple daily injections: Basal insulin is given once or twice daily, and bolus insulin typically injected at meals three or more times daily based on carbohydrate content and current blood glucose.
  • Insulin pumps: They deliver rapid-acting insulin only and provide a basal rate of insulin that is either programmed or automatically adjusted based on continuous glucose monitor input in some pumps, and mealtime insulin is typically calculated based on mealtime inputs of carbohydrate and current blood glucose.
• Honeymoon period: Patients usually have some remaining beta cells at the time of diagnosis of the diabetes. Hence, insulin requirements often decline temporarily 1 to 3 months after diagnosis. During this honeymoon period, dose requirements may drop to less than 0.5 units/kg/day which may lasts several months occasionally for 12 months or more. However, most patients who have type 1 diabetes have no significant insulin production except during the honeymoon period; therefore, most preadolescent children need about 0.5 to 1.0 units/kg/day and adolescents usually requires about 0.8 to 1.2 units/kg/day due to increased insulin resistance during puberty.
• Insulin: All insulin is manufactured by recombinant DNA technology based on the amino acid sequence of human insulin which are elaborated in Table 4.

Table 4: Types of insulin preparations and approximate insulin action profiles

Insulin type	Onset of action (h)	Peak of action (h)	Duration of action (h)
Rapid-acting analogs Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra)	0.25–0.5 0.25–0.5 0.25–0.5	1–3 1–3 1–3	3–5 3–5 3–5
Regular insulin	0.5–1	2–4	5–8
Intermediate-acting: NPH	2–4	4–8	12–18
Long-acting analogs Detemir (Levemir) Glargine (Lantus, Basaglar, Toujeo) Degludec (Tresiba)	2–4 2–4 2–4	none none none	12–24 up to 24 ›24

• Split/mixed regimens: It require at least two injections per day of short- and intermediate-acting insulin (a mix of NPH and regular/rapid) being administered shortly before breakfast and dinner to achieve satisfactory metabolic control. When split/mixed regimens are used, patients usually need about two thirds of their total dose in the morning and one third in the evening. The doses usually are split between one-third regular/rapid-acting insulin and two thirds NPH to one-half/one-half. More regular/rapid-acting insulin may be required in the morning because of the dawn phenomenon which is caused by normal nocturnal increases in some counter-regulatory hormones that lead to reduced insulin sensitivity in the early morning.

• Basal/bolus regimens: It aims to achieve more physiologic insulin concentrations with less between-meal insulin action.
  • Basal insulin: It provides baseline or fasting insulin needs, which are usually about 50% of total daily insulin requirements, by either rapid-acting insulin given with the basal rate of an insulin pump or with once- or twice daily injections of detemir or glargine.
  • Bolus insulin: It is provided by acute doses of rapid-acting insulin either through injections or through bolus doses given by an insulin pump to cover food requirements and to correct hyperglycemia. It has two parts to the dose: the amount of insulin needed to cover the carbohydrates in the meal and the amount of insulin needed to correct for a blood glucose concentration outside of the target range.
  • The Basal/bolus doses are based on empiric formulas, and modifications can be made once responses to starting doses are assessed.
  • The insulin-to-carbohydrate ratio, which may differ for each patient and for different times of day, is the insulin requirement for each gram of carbohydrate in a meal.
  • The correction or sensitivity factor is how much the individual patient’s blood glucose values fall when given 1 unit of insulin.
  • Thus, the premeal bolus dose equals the insulin-to-carbohydrate ratio multiplied by the grams of carbohydrate to be eaten plus the insulin sensitivity factor multiplied by the amount that the blood glucose needs to fall from the preprandial value to reach the target range.
  • Target ranges, for example, may be set at 80 to 120 mg/dL (4.4 to 6.7 mmol/L) for daytime and 100 to 150 mg/dL (5.6 to 8.3 mmol/L) at bedtime. When converting a child from a two- or three-injection regimen with NPH to a basal/bolus regimen, the total daily dose is usually lower, and recommendations are to use 50% to 80% of the NPH dose for the initial basal insulin dose, with the lower percentages used for younger children.

• Automated Insulin Delivery: The combination of continuous glucose sensors with insulin pumps has enabled the development of automated insulin delivery systems (“closed-loop” or “artificial pancreas” devices). “Hybrid” closed-loop systems, which modulate basal insulin delivery based on sensor glucose levels, have increased time spent within target glucose ranges, reduced hyper- and hypoglycemia exposure, lowered A1C levels, and improved measures of quality of life in both adult and adolescent subjects. However, transition of automated insulin delivery from research to clinical care will require patient and provider education to optimize outcomes.

• Adjunctive therapies: Pramlintide, an analog of the pancreatic polypeptide amylin, has been shown to improve glycemic control when added to insulin in adults with type 1 diabetes primarily through dampening glycemic excursions by suppressing glucagon secretion and delaying gastric emptying. However, neither pramlintide nor other potentially useful adjuncts, such as glucagon like peptide 1 receptor agonists (e.g., liraglutide, exenatide) or sodium–glucose cotransporter 2 inhibitors, have been thoroughly studied in the pediatric population with type 1 diabetes, and none have been approved yet for use in this population by the FDA.

Type 2 Diabetes Mellitus

• Pharmacological agents: Metformin and insulin are the only medications for use in children and adolescents.
  • Metformin: It is first-line therapy along with in combination with diet and exercise in children 10 years and older. It should be initiated at a dosage of 500 mg per day, regardless of the patient’s weight, then titrated in 500 mg intervals over four weeks to the maximum dosage of 2,000 mg per day. The gradual increase of the medication and taking it with food helps to prevent gastrointestinal side effects.
  • Insulin: Insulin may be beneficial for these patients on a short-term basis; subsequently can be discontinued after initiating metformin therapy and lifestyle changes. A basal/bolus regimen like in T1DM may be used, but typically T2DM patients require higher doses (2-3 unit/kg/day). However, it must be initiated in the following scenarios:
    • Patient has signs of ketosis or ketoacidosis
    • Random plasma glucose levels of 250 mg/dL (13.9 mmol/L) or greater
    • A1C level is greater than 9%
    • Diagnosis of type 1 vs. type 2 is not clear.

Lifestyle management

• Lifestyle management is important for pediatric patients with diabetes to enable health maintenance, CVD prevention, and glycemic control.

Nutrition

• Dietary management should be individualized: family habits, food preferences, religious or cultural needs, schedules, physical activity, and the patient’s and family’s abilities in numeracy, literacy, and self-management level.
• Dietitian visits should include assessment for changes in food preferences over time, access to food, growth and development, weight status, cardiovascular risk, and potential for eating disorders.
• Current consensus recommends the following:
  • Carbohydrates: 50-55% of the daily energy intake but simple carbohydrates like sucrose should not make up more than 10% of the total.
  • Fats: ~30% of the daily energy intake.
  • Protein: 10-15% of the daily energy intake.
• Most carbohydrate calories should be complex carbohydrates, and the fat portion should emphasize low amounts of cholesterol and saturated fats.
• Split/ mixed insulin regimens: For patients using this regimen, timing of meals is important to minimize blood glucose variability.
  • Mid-afternoon snacks: In addition to the usual three meals, they are necessary because they coincide with the typical peak of the morning NPH insulin dose and with most after-school sports activities.
  • Bedtime snacks: They are important for most children receiving evening NPH doses.
  • Midmorning snacks: They are useful in preschool-age children, but most school-age children find such snacks disruptive to their school routine. This snack usually is not recommended after a child begins elementary school.

Physical activity and Exercise

• Exercise is recommended with the goal of 60 min of moderate- to vigorous intensity aerobic activity daily along with vigorous muscle-strengthening and bone-strengthening activities at least 3 days per week.
• Hypoglycemia during exercise:
  • Deranged intrinsic balance: The type, intensity, and duration of exercise trigger the release of multiple hormones such as insulin, glucagon, catecholamines, and glucocorticoids to mediate the fuel metabolism. Pancreatic islet cells achieve euglycemia by balancing peripheral glucose uptake and hepatic glucose production. However, this intrinsic balance does not exist in T1DM. Exogenous insulin administration inhibits hepatic glucose production and promotes exercise-induced glucose uptake, thereby both triggering hypoglycemia.
  • Lag effect: Intense exercise increases hypoglycemia risk during, immediately following, and 6–12 h after physical activity namely the “lag effect”. This lag likely results from a combination of improved insulin sensitivity following exercise, blunted counterregulatory hormone release, and increased glucose uptake bythe liver and skeletal muscles to replenish glycogen stores. Impaired counterregulatory hormone release in pediatric patients may include blunting during sleep, antecedent hypoglycemia, and autonomic failure. Delayed hypoglycemia often occurs at night following afternoon physical activities. Therefore, exercise-induced hypoglycemia and fear of hypoglycemia may limit desire to participate in exercise.
  • Preventive measures: Education about prevention and management of potential hypoglycemia during and after exercise is essential, including pre-exercise glucose levels of 90–250 mg/dL (5–13 mmol/L) and accessible carbohydrates snacks, individualized according to the type/intensity of the planned physical activity. Strategies to prevent hypoglycemia during exercise, after exercise, and overnight following exercise are as follows:
    • Reduce prandial insulin dosing for the meal/snack preceding exercise
    • Increase carbohydrate intake
    • Eating bedtime snacks
    • Use of CGM
    • Reduce basal insulin doses
    • 10-15 g of carbohydrate may prevent hypoglycemia during low- to moderate-intensity aerobic activities (30-60 min) in fasting patient
    • 0.5–1.0 g of carbohydrates/kg per hour of exercise (~30-60 g) may prevent hypoglycemia due to relative hyperinsulinemia after insulin boluses which is similar to carbohydrate requirements to optimize performance in athletes without T1DM.
• Hyperglycemia during exercise: It may occur during high-intensity exercise such as sprints or resistance training when there is inadequate delivery of exogenous insulin and/or an excess of counterregulatory hormones that increase hepatic glucose production and inhibit glucose uptake into skeletal muscle. Intense activity should be postponed with marked hyperglycemia (glucose≥350mg/dL [19.4mmol/L]), moderate to large urine ketones, and/or b-hydroxybutyrate ›1.5 mmol/L. Caution may be needed when b-hydroxybutyrate levels are ≥0.6 mmol/L.
• Hence, frequent glucose monitoring before, during, and after exercise, with or without CGM use, is important to prevent, detect, and treat hypoglycemia and hyperglycemia with exercise.

Education and Family involvement

• Diabetes comprehensive education about the disease aspects and its potential acute and long-term complications is life-long for patients, families, and the diabetes team.
• They must understand details of insulin action, including duration and timing and dose adjustments, injection and insertion techniques, electronics and mechanics of insulin pumps, dietary information, blood glucose monitoring and interpretation, and urine ketone checks and appropriate interventions.
• Family-centered education is culturally appropriate to improve medication adherence and successful implications of lifestyle changes.
• Education about diabetes must be appropriate to the child’s age and the family’s educational background. Responsibility for diabetes self-care skills (eg, insulin injections) should be shifted gradually from parent to child, and when the child shows interest and readiness to take responsibility. Premature shifting of responsibility may result in deterioration of metabolic control. Sharing responsibilities and attending support groups and camps for children who have T1DM can help with psychological adjustment. The psychosocial effects of diabetes should be addressed to help children and adolescents cope with the disease.

Assessment of Glycemic control

• A1C monitoring: It should be measured at 3-month intervals to assess their overall glycemic control with a target of ‹7.5%; but should be individualized based on the needs and situation of the patient and family. With increasing use of continuous glucose monitoring (CGM) devices, outcomes other than A1C, such as time with glucose in target range and frequency of hypoglycemia, should be considered in the overall assessment of glycemic control.
• Blood glucose monitoring: Blood glucose levels should be monitored multiple times daily up to 6–10 times/day including premeal and pre-bedtime; and as needed for safety reasons in specific situations such as exercise, driving, illness, or the presence of hypoglycemic symptoms.
• Blood/Urinary Ketone Monitoring: Blood or urine ketone levels should be measured in the setting of prolonged/severe hyperglycemia or acute illness to determine if treatment adjustment or urgent care referral is needed.
• Continuous glucose monitoring (CGM): CGM should be considered in all children and adolescents with T1DM, whether using injections or insulin pump therapy, as an additional tool to help improve glycemic control.

Anticipatory Guidance

• Immunization: Diabetic children should receive all immunizations in accordance with the recommendations of the Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention; including annual vaccination against influenza for children with DM who are at least 6 months of age, and one dose of 23-valent pneumococcal polysaccharide vaccine (Pneumovax) at least eight weeks after previous dose of 13-valent pneumococcal conjugate vaccine (Prevnar 13). The child and adolescent vaccination schedule is available at www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html

• Growth: Normal linear growth and appropriate weight gain throughout childhood and adolescence are considered as a measurement markers of general health and metabolic control. Height and weight should be tracked via appropriate growth charts at regular visit available at www.cdc.gov/growthcharts/clinical_charts.htm. Overweight and obesity are emerging issues in youth with T1DM and should be considered as part of dietary counseling.

• Multidisciplinary evaluation: All people with diabetes should have regular dilated eye exams (to examine for diabetic retinopathy), urine microalbumin screening (to evaluate for renal involvement), hyperlipidemia screens/treatment, hypertension screening/treatment, liver function tests, sleep apnea evaluation, and regular assessment of psychosocial adherence, self-management skills, dietary needs, and physical activity level at appropriate intervals.

• Smoking: Elicit a smoking history at initial and follow-up diabetes visits; discourage smoking in youth who do not smoke; and encourage smoking cessation in those who do smoke and referral to an appropriate smoking cessation program should be given.

• Transition from pediatric to adult care: Pediatric diabetes providers should begin to prepare youth for transition in early adolescence at least 1 year before the transition to adult health care. Both pediatric and adult diabetes care providers should provide support and resources for transitioning young adults.